[go: up one dir, main page]

CN103282052B - Aqueous ophthalmic compositions - Google Patents

Aqueous ophthalmic compositions Download PDF

Info

Publication number
CN103282052B
CN103282052B CN201180063560.6A CN201180063560A CN103282052B CN 103282052 B CN103282052 B CN 103282052B CN 201180063560 A CN201180063560 A CN 201180063560A CN 103282052 B CN103282052 B CN 103282052B
Authority
CN
China
Prior art keywords
aqueous ophthalmic
ophthalmic compositions
castor oil
terpenoid
polyoxyethylene castor
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN201180063560.6A
Other languages
Chinese (zh)
Other versions
CN103282052A (en
Inventor
古宫千夏
宫野贵之
中田温子
松本江利
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Rohto Pharmaceutical Co Ltd
Original Assignee
Rohto Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Rohto Pharmaceutical Co Ltd filed Critical Rohto Pharmaceutical Co Ltd
Publication of CN103282052A publication Critical patent/CN103282052A/en
Application granted granted Critical
Publication of CN103282052B publication Critical patent/CN103282052B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Molecular Biology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Biochemistry (AREA)
  • Inorganic Chemistry (AREA)
  • Biophysics (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Medicinal Preparation (AREA)

Abstract

The invention provides a kind of aqueous ophthalmic compositions, the average addition molal quantity of it contains (A) ethylene oxide is polyoxyethylene castor oil and (B) terpenoid of 2 ~ 12.According to the present invention, the aqueous ophthalmic compositions that antifoaming speed is improved can be obtained.

Description

Aqueous ophthalmic compositions
Technical field
The present invention relates to aqueous ophthalmic compositions.
Background technology
In field of ophthalmology, solubilizing agent is compounded in a lot of prescription.Especially, in aqueous ophthalmic compositions, for the purpose of the physiologically active ingredient lower by assist in dissolving water solublity or additive etc., compounding various solubilizing agent is managed.As one of solubilizing agent used in field of ophthalmology, surfactant can be listed.Known compoundingly have the aqueous formulation of surfactant easily to bubble, during fabrication or circulation time, vibrated or impacted and will be bubbled.
Generally speaking, in order to make aqueous ophthalmic compositions be applied to eyes safely, dissolving when it manufactures confirms to come into one's own.In addition, to medicines such as the eye drop in aqueous ophthalmic compositions, collyriums, the inspection of foreign substance in manufacturing process is absolutely necessary.But present situation is, when producing foam in the aqueous ophthalmic compositions in manufacture process and antifoaming speed is low, because compounding ingredients or foreign body are difficult to distinguish with foam, therefore dissolving confirmation, inspection of foreign substance operation etc. need the time long, and manufacture cannot be carried out expeditiously.
On the other hand, be compounded in for the purpose of refrigerant sense when terpenoid is to bring application sometimes (with reference to patent documentation 1) in ophthalmic composition.But, when the known ophthalmic composition storage by containing terpenoid is preserved in a reservoir, the concentration of terpenoid can through time reduce.Infer that its reason is, terpenoid is adsorbed on container or the volatilization etc. of terpenoid, but also finds no the solution of effect at present.
Prior art document
Patent documentation
Patent documentation 1: Japanese Unexamined Patent Publication 2004-315517 publication
Summary of the invention
the problem that invention will solve
The present invention completes in view of the present situation of above-mentioned prior art, its main purpose is, for aqueous ophthalmic compositions, especially compounding aqueous ophthalmic compositions that have the solubilizing agents such as surfactant, that easily bubble, is vibrated or is impacted even if provide a kind of and produced foam but the also fast aqueous ophthalmic compositions of this antifoaming speed.
Other main purpose of the present invention is for the aqueous ophthalmic compositions containing terpenoid, provide a kind of suppress terpenoid substrate concentration through time the method that reduces.
And then other object of the present invention is to provide a kind of aqueous ophthalmic compositions, it has the various effects improved further.
for the scheme of dealing with problems
The present inventor etc. conduct in-depth research to solve above-mentioned problem, the discovery of shock: by simultaneously compounding specific polyoxyethylene castor oil and terpenoid in hydrotropism's ophthalmic composition, when it is vibrated or impacts and produce foam, this antifoaming speed improves significantly.And then, find to use when being in the aqueous ophthalmic compositionss such as the eye drop of a large amount of bubblement during the research such as the present inventor, technical problem that its each dropping liquid amount deviation is large.Especially to releive liquid for the less eye drop of single use amount, contact lens, this technical problem is particularly serious.If the deviation of dropping liquid amount is large, is difficult to control each use amount, the inconvenience such as not easy to operate due to user self can be produced, especially when this aqueous ophthalmic compositions is medicine, also may involves the reduction etc. of interdependence.But aqueous ophthalmic compositions according to the present invention can also suppress the deviation of this dropping liquid amount.
In addition, the present inventor etc. find, by simultaneously compounding terpenoid and specific polyoxyethylene castor oil, can play the effect of the concentration reduction suppressing the terpenoid be accommodated in the aqueous ophthalmic compositions in container.
In addition, the research according to the present inventor etc. finds, so and with the preservation effect of the aqueous ophthalmic compositions of specific polyoxyethylene castor oil and terpenoid obtains and strengthens.In general, known nonionic surfactant has antiseptic deactivation, the effect reducing its antiseptic power.Therefore, using when combinationally using as the specific polyoxyethylene castor oil of nonionic surfactant and terpenoid, its preservation effect obtains that to strengthen be beyond thought effect completely.
In addition, the present inventor etc. are surprised to find that through repeatedly studying, although the average addition molal quantity of ethylene oxide is that the water solublity of the polyoxyethylene castor oil of 2 ~ 12 is low, easily separated in aqueous, but it is jointly compounding by the terpenoid low with same water solublity, two kinds of composition separation in aqueous ophthalmic compositions are all suppressed, can use steadily in the long term.Namely, research according to the present inventor etc. finds, although easily separated or separate out in above-mentioned specific polyoxyethylene castor oil and each comfortable aqueous ophthalmic compositions of terpenoid, but shock is by common compounding use polyoxyethylene castor oil and terpenoid, can play the effect suppressing it to be separated simultaneously.
The present invention forms according to the result that the basis found at these is studied further repeatedly.
That is, the invention provides the ophthalmic composition of following proposal.
1-1. aqueous ophthalmic compositions, the average addition molal quantity of it contains (A) ethylene oxide is polyoxyethylene castor oil and (B) terpenoid of 2 ~ 12.
The 1-2. aqueous ophthalmic compositions according to item 1-1, wherein, (A) composition is be selected from least one in the group that is made up of polyoxyethylene castor oil 3 and polyoxyethylene castor oil 10.
The 1-3. aqueous ophthalmic compositions according to item 1-1 or 1-2, wherein, relative to the total amount of aqueous ophthalmic compositions, (A) composition containing proportional be 0.01 ~ 3w/v%.
The 1-4. aqueous ophthalmic compositions according to any one in item 1-1 to 1-3, wherein, (B) composition is be selected from least one in the group that is made up of menthol, Camphora, geraniol, Borneolum Syntheticum and eucalyptus oil.
The 1-5. aqueous ophthalmic compositions according to any one in item 1-1 to 1-4, wherein, relative to the total amount of aqueous ophthalmic compositions, (B) composition containing proportional be 0.0001 ~ 1w/v%.
The aqueous ophthalmic compositions of item 1-6. according to item 1-1 to 1-5, wherein, relative to total amount 100 weight portion of (A) composition, the total amount of (B) composition is 0.01 ~ 1000 weight portion.
The aqueous ophthalmic compositions of item 1-7. according to item 1-1 to 1-6, wherein, relative to total amount 100 weight portion of (A) composition, the total amount of (B) composition is 2 ~ 15 weight portions.
The aqueous ophthalmic compositions of item 1-8. according to any one in item 1-1 to 1-7, it is also containing buffer agent.
The aqueous ophthalmic compositions of item 1-9. according to any one in item 1-1 to 1-8, wherein, buffer agent is borate buffer.
The 1-10. aqueous ophthalmic compositions according to item 1-8 or 1-9, wherein, relative to the total amount of aqueous ophthalmic compositions, buffer agent containing proportional be 0.01 ~ 10w/v%.
The aqueous ophthalmic compositions of item 1-11. according to any one in item 1-1 to 1-10, it is also containing the nonionic surfactant beyond (A) composition.
The aqueous ophthalmic compositions of item 1-12. according to item 1-11, wherein, the nonionic surfactant beyond (A) composition is at least one in the group that forms of polyoxyethylene castor oil that to be selected from by the average addition molal quantity of polyoxyethylene sorbitan fatty acid ester, polyoxyethylene hydrogenated Oleum Ricini, polyoxyethylene polyoxypropylene block copolymer and ethylene oxide be more than 20.
The 1-13. aqueous ophthalmic compositions according to item 1-11 or 1-12, wherein, relative to the total amount of aqueous ophthalmic compositions, the nonionic surfactant beyond (A) composition containing proportional be 0.001 ~ 3w/v%.
The aqueous ophthalmic compositions of item 1-14. according to any one in item 1-1 to 1-13, it is filled in polyethylene terephthalate container and forms.
The aqueous ophthalmic compositions of item 1-15. according to any one in item 1-1 to 1-14, it is filled in the container being provided with polyethylene nozzle and forms.
The aqueous ophthalmic compositions of item 1-16. according to any one in item 1-1 to 1-15, it is eye drop.
The aqueous ophthalmic compositions of item 1-17. according to any one in item 1-1 to 1-15, it is collyrium.
The 1-18. aqueous ophthalmic compositions according to any one in item 1-1 to 1-15, it to be releived liquid for contact lens.
The aqueous ophthalmic compositions of item 1-19. according to any one in item 1-1 to 1-15, it is contact lens care agent.
In addition, the invention provides following shown in form raising aqueous ophthalmic compositions in the method for antifoaming speed, and the method for the deviation of dropping liquid amount when suppressing to use.
Item 2. 1 kinds improves the method for antifoaming speed in aqueous ophthalmic compositions, and it comprises: the average addition molal quantity of compounding in hydrotropism's ophthalmic composition (A) ethylene oxide is polyoxyethylene castor oil and (B) terpenoid of 2 ~ 12.
The 3. 1 kinds methods improving antifoaming speed in aqueous ophthalmic compositions, it comprises: be compounding (B) terpenoid in the aqueous ophthalmic compositions of the polyoxyethylene castor oil of 2 ~ 12 to the average addition molal quantity containing (A) ethylene oxide.
The 4. 1 kinds methods suppressing the aqueous ophthalmic compositions deviation of dropping liquid amount in use, it comprises: the average addition molal quantity of compounding in hydrotropism's ophthalmic composition (A) ethylene oxide is polyoxyethylene castor oil and (B) terpenoid of 2 ~ 12.
Item 5. 1 kinds improves the method for antifoaming speed in aqueous ophthalmic compositions, and it comprises: in the aqueous ophthalmic compositions containing the surfactant beyond (A) composition, the average addition molal quantity of compounding (A) ethylene oxide is polyoxyethylene castor oil and (B) terpenoid of 2 ~ 12.
The 6. 1 kinds methods suppressing the aqueous ophthalmic compositions deviation of dropping liquid amount in use, it comprises: in the aqueous ophthalmic compositions containing the surfactant beyond (A) composition, the average addition molal quantity of compounding (A) ethylene oxide is polyoxyethylene castor oil and (B) terpenoid of 2 ~ 12.
In addition, the invention provides the method for the preservation effect of the enhancing aqueous ophthalmic compositions of following shown form.
Item 7. 1 kinds strengthens the method for the preservation effect of aqueous ophthalmic compositions, and it comprises: the average addition molal quantity of compounding in hydrotropism's ophthalmic composition (A) ethylene oxide is polyoxyethylene castor oil and (B) terpenoid of 2 ~ 12.
The 8. 1 kinds methods strengthening the preservation effect of aqueous ophthalmic compositions, it comprises: to being the polyoxyethylene castor oil of 2 ~ 12 containing the average addition molal quantity of compounding (A) ethylene oxide in the aqueous ophthalmic compositions of (B) terpenoid.
In addition, the invention provides the method for the separation of the suppression aqueous ophthalmic compositions of following shown form.
Item 9. 1 kinds suppresses the method for the separation of aqueous ophthalmic compositions, and it comprises: the average addition molal quantity of compounding in hydrotropism's ophthalmic composition (A) ethylene oxide is polyoxyethylene castor oil and (B) terpenoid of 2 ~ 12.
The 10. 1 kinds methods suppressing the separation of aqueous ophthalmic compositions, it comprises: be compounding (B) terpenoid in the aqueous ophthalmic compositions of the polyoxyethylene castor oil of 2 ~ 12 to the average addition molal quantity containing (A) ethylene oxide.
The 11. 1 kinds methods suppressing the separation of aqueous ophthalmic compositions, it comprises: to being the polyoxyethylene castor oil of 2 ~ 12 containing the average addition molal quantity of compounding (A) ethylene oxide in the aqueous ophthalmic compositions of (B) terpenoid.
In addition, the invention provides following shown in form suppression terpenoid through time concentration reduce method.
12. 1 kinds suppression be accommodated in the terpenoid substrate concentration of the aqueous ophthalmic compositions in container through time the method that reduces, it comprises: the average addition molal quantity of compounding in hydrotropism's ophthalmic composition (A) ethylene oxide is polyoxyethylene castor oil and (B) terpenoid of 2 ~ 12.
13. suppression terpenoid substrate concentrations according to item 12 through time the method that reduces, wherein, the container of storage aqueous ophthalmic compositions is the polyethylene terephthalate container being provided with polyethylene nozzle.
14. 1 kinds give aqueous ophthalmic compositions with suppress the terpenoid substrate concentration of this aqueous ophthalmic compositions be accommodated in container through time the method for effect that reduces, it comprises: to being the polyoxyethylene castor oil of 2 ~ 12 containing the average addition molal quantity of compounding (A) ethylene oxide in the aqueous ophthalmic compositions of (B) terpenoid.
15. imparting aqueous ophthalmic compositionss according to item 14 with suppresses terpenoid substrate concentration through time reduction the method for effect, wherein, the container receiving aqueous ophthalmic compositions is the polyethylene terephthalate container being provided with polyethylene nozzle.
In addition, the invention provides the method for the refrigerant sense of the maintenance aqueous ophthalmic compositions of following shown form.
Item 16. 1 kinds maintains the method for the refrigerant sense of aqueous ophthalmic compositions, and it comprises: the average addition molal quantity of compounding in hydrotropism's ophthalmic composition (A) ethylene oxide is polyoxyethylene castor oil and (B) terpenoid of 2 ~ 12.
And then the present invention also provides purposes as follows.
The average addition molal quantity of item 17. (A) ethylene oxide is the polyoxyethylene castor oil of 2 ~ 12 and the purposes for the manufacture of aqueous ophthalmic compositions of (B) terpenoid.
The purposes of item 18. according to item 17, wherein, aqueous ophthalmic compositions is the compositions described in any one in above-mentioned item 1-1 to 1-19.
And then the present invention also provides the purposes of form as follows.
19. 1 kinds average addition molal quantitys comprising (A) ethylene oxide be the polyoxyethylene castor oil of 2 ~ 12 and the compositions of (B) terpenoid, as the purposes of aqueous ophthalmic compositions.
The purposes of item 20. according to item 19, wherein, compositions is the compositions described in any one in above-mentioned item 1-1 to 1-19.
And then the present invention also provides the compositions of following shown form.
Item 21. 1 kinds of compositionss, it is used as aqueous ophthalmic compositions, and the average addition molal quantity comprising (A) ethylene oxide is polyoxyethylene castor oil and (B) terpenoid of 2 ~ 12.
The compositions of item 22. according to item 21, it is the compositions described in any one in above-mentioned item 1-1 to 1-19.
And then the present invention also provides the manufacture method of the aqueous ophthalmic compositions of following shown form.
The manufacture method of 23. 1 kinds of aqueous ophthalmic compositionss, it comprises: the average addition molal quantity adding (A) ethylene oxide in the carrier comprising water is polyoxyethylene castor oil and (B) terpenoid of 2 ~ 12.
The manufacture method of item 24. according to item 23, wherein, aqueous ophthalmic compositions is the compositions described in any one in above-mentioned item 1-1 to 1-19.
the effect of invention
According to the present invention, following various effects can be realized.
(1) according to the present invention, by being also polyoxyethylene castor oil and the terpenoid of 2 ~ 12 with the average addition molal quantity of ethylene oxide, the antifoaming speed of aqueous ophthalmic compositions can be improved.Dissolving confirmation when result can complete the manufacture of aqueous ophthalmic compositions at short notice or foreign body confirm, can improve manufacture efficiency.
(2) aqueous ophthalmic compositions of the present invention can by there is above-mentioned feature suppress use time due to the deviation of dropping liquid amount caused of bubbling.Therefore, use amount is easy to control, and concerning user, be convenient to process, interdependence improves.
(3) preservation effect of aqueous ophthalmic compositions of the present invention obtains and strengthens.Therefore, even if requiring in the field of ophthalmology to safety high in germ contamination, the pollution of aqueous ophthalmic compositions when also can reduce use, the risk etc. of infected by microbes disease caused thus.
(4) according to aqueous ophthalmic compositions of the present invention, when can suppress to be accommodated in container terpenoid substrate concentration through time reduce.Therefore, refrigerant sense and effect of the present invention that terpenoid brings can be played steadily in the long term.
(5) aqueous ophthalmic compositions of the present invention can the average addition molal quantity of inhibited oxidation ethylene be the separation of the refractory components such as polyoxyethylene castor oil, terpenoid of 2 ~ 12.Therefore, the physical property of aqueous ophthalmic compositions can be made to maintain a long-term stability.
(6) aqueous ophthalmic compositions of the present invention maintains refrigerant sense in use.Therefore, the experience of user is good, can cosily use aqueous ophthalmic compositions.
Aqueous ophthalmic compositions of the present invention is the compositions with above-mentioned various excellent effect, can safer and comfortable, use long-term effectively.
Detailed description of the invention
The unit " % " of the compounding ratio in this description refers to " w/v% ", with " g/100mL " synonym.
In this description, if record without special, then abridge " POE " refers to polyoxyethylene.
In this description, if record without special, then abridge " POP " refers to polyoxypropylene.
In this description, if record without special, contact lens refer to comprise rigid, oxygen permeability is rigid, soft (containing silicone hydrogel lens), all types of contact lens such as colored.
[1. aqueous ophthalmic compositions]
The average addition molal quantity that aqueous ophthalmic compositions of the present invention contains ethylene oxide is the polyoxyethylene castor oil (following, to be sometimes simply designated as (A) composition) of 2 ~ 12.By using the polyoxyethylene castor oil of this specific ethylene oxide addition molal quantity, and by itself and terpenoid described later and use, thus the excellent effect of the invention described above can be given play to.
Polyoxyethylene castor oil is the known compound obtained by adding polyethylene glycol oxide to Oleum Ricini, there will be a known several kinds that the average addition molal quantity of ethylene oxide is different.Average addition molal quantity as the ethylene oxide of the polyoxyethylene castor oil of (A) of the present invention composition use is 2 ~ 12 moles.The polyoxyethylene castor oil 10 etc. that the average addition molal quantity that specifically can list ethylene oxide is the polyoxyethylene castor oil 3 of 3, the average addition molal quantity of ethylene oxide is 10.
These polyoxyethylene castor oils can be used alone one, also can be used in combination arbitrarily.In addition, polyoxyethylene castor oil used in the present invention is the compound different from the polyoxyethylene hydrogenated Oleum Ricini obtained by adding polyethylene glycol oxide to castor oil hydrogenated, needs to distinguish.
In aqueous ophthalmic compositions of the present invention, (A) kind containing proportional basis (A) composition of composition, and the kind of (B) composition, the dosage form of this aqueous ophthalmic compositions etc. are setting suitably, as an example, the total amount relative to aqueous ophthalmic compositions can be exemplified, (A) total amount of composition is 0.01 ~ 3w/v%, be preferably 0.02 ~ 2w/v%, be more preferably 0.02 ~ 1w/v%, more preferably 0.05 ~ 1w/v%, more preferably 0.05 ~ 0.6w/v%, more preferably 0.2 ~ 0.6w/v%, be particularly preferably 0.2 ~ 0.4w/v%, most preferably be 0.2 ~ 0.3w/v%%.
In addition, in aqueous ophthalmic compositions of the present invention, consider from the angle suppressing aqueous ophthalmic compositions to be bubbled, such as preferred 0.05 ~ 0.3w/v%, consider from the angle of the preservation effect of aqueous ophthalmic compositions, such as preferred 0.025 ~ 0.4w/v%.
From improve aqueous ophthalmic compositions antifoaming speed effect, suppress to use time dropping liquid amount the effect of deviation, the raising effect of preservation effect or improve further and be separated inhibiting viewpoint, above-mentioned (A) composition containing proportional be applicable.In addition, from the viewpoint of improve further suppress the concentration of the terpenoid be accommodated in container through time the effect that reduces, be also applicable.
Ophthalmic composition of the present invention needs on the basis of above-mentioned (A) composition, containing terpenoid (being also sometimes designated as (B) composition below).By so also using (A) composition and (B) composition, above-mentioned effect can be played, that is, improve antifoaming speed, suppress the deviation of dropping liquid amount when using, suppress the concentration of terpenoid through time the effect that reduces, strengthen preservation effect, suppress the separation of refractory components etc.
As the terpenoid that (B) composition uses, as long as pharmaceutically, the pharmacologically upper material allowed of (in pharmacy) or physiology, be then not particularly limited.As this terpenoid, menthol, Camphora, Borneolum Syntheticum, geraniol, eucalyptole, citronellol, menthone, carvone, anethole, acetaminol, limonene, linalool, linalyl acetate, their derivant etc. specifically can be listed.These compounds can be any one of d body, l body or dl body.In addition, in the present invention, as terpenoid, the quintessence oil containing above-claimed cpd can also be used.As such quintessence oil, include, for example out eucalyptus oil, oleum bergamottae, mentha piperita oil (peppermint oil), cool peppermint oil, Oleum Menthae Rotundifoliae, Oleum menthae (mint oil), Oleum Anisi Stellati, Oleum Cinnamomi, Flos Rosae Rugosae wet goods.These terpenoids can be used alone one, also can be used in combination arbitrarily.
In these (B) compositions, from the viewpoint better playing effect of the present invention, preferably can list menthol, Camphora, geraniol, Borneolum Syntheticum etc., cool peppermint oil, mentha piperita oil, Oleum menthae, Oleum Camphora, Folium eucalypti globueli (Eucalyptus globulus Labill.) wet goods can be exemplified as the preferred quintessence oil containing these.More preferably menthol, Camphora, geraniol, Borneolum Syntheticum, eucalyptus oil can be listed; Preferably can list l-menthol, d-Camphora, dl-Camphora, geraniol, d-Borneolum Syntheticum and eucalyptus oil further.
In aqueous ophthalmic compositions of the present invention, proportional about containing of (B) composition, from the viewpoint playing effect of the present invention better, relative to the total amount of aqueous ophthalmic compositions, the total amount that can list (B) composition is 0.0001 ~ 1w/v%, is preferably 0.001 ~ 0.1w/v%, is more preferably 0.003 ~ 0.06w/v%, more preferably 0.003 ~ 0.02w/v%.In addition, as above-mentioned (B) composition, when using containing the quintessence oil of terpenoid, meet to make the total amount of the terpenoid content in compounding quintessence oil and above-mentionedly to set containing proportional mode.
In ophthalmic composition of the present invention, for (B) composition for the ratio of (A) composition, as long as meet above-mentioned containing proportional, be not particularly limited, but in order to give full play to above-mentioned effect of the present invention, namely, improve antifoaming speed, the deviation of dropping liquid amount when suppressing to use, suppress terpenoid concentration through time reduce, strengthen preservation effect, suppress the effect of the separation of refractory components etc., preferably meet following ratio: relative to total amount 100 weight portion of (A) composition, (B) total amount of composition reaches 0.01 ~ 1000 weight portion, preferably reach 0.1 ~ 500 weight portion, more preferably 0.5 ~ 100 weight portion is reached, preferably reach 0.5 ~ 80 weight portion further, particularly preferably reach 0.5 ~ 50 weight portion, most preferably reach the ratio of 1 ~ 25 weight portion.Especially, when ratio is total amount 100 weight portion relative to (A) composition, when the total amount of (B) composition reaches the ratio of 2 ~ 15 weight portions, above-mentioned effect can play admirably.
Aqueous ophthalmic compositions of the present invention as shown in the above, can according to its application target, can compounding various pharmacological component, physiologically active ingredient etc., but also can compounding various additive.In this case, in order to improve the dissolubility of physiologically active ingredient, additive etc., as solubilizing agent, preferably other surfactant compounding further beyond (A) composition.During compounding such surfactant, usually rise to steep oneself-meeting and increase, but according to the present invention, even the surfactant beyond compounding (A) composition causes aqueous ophthalmic compositions easy to foaming, by according to above-mentioned standard compounding (A) composition and (B) composition simultaneously, can antifoaming speed be improved, improve and manufacture efficiency, and then suppress the deviation of dropping liquid amount.In addition, can improve further suppress terpenoid concentration through time reduce wait, effect of the present invention.
As can compounding in aqueous ophthalmic compositions of the present invention, surfactant beyond (A) composition, as long as pharmaceutically, pharmacologically the upper material allowed of (in pharmacy) or physiology be then not particularly limited, can be nonionic surfactant, amphoteric surfactant, anionic surfactant, cationic surface active agent any one.
As can be compounding to the nonionic surfactant in aqueous ophthalmic compositions of the present invention, the POE sorbitan fatty acid ester classes such as POE (20) Span-20 (polysorbate20), POE (20) sorbitan monopalmitate (polysorbate40), POE (20) sorbitan monostearate (polysorbate60), POE (20) sorbitan tristearate (polysorbate65), POE (20) sorbitan monooleate (polysorbate80) specifically can be exemplified; The POE castor oil hydrogenated such as POE (60) castor oil hydrogenated (HCO60); The POE alkyl ethers such as POE (9) lauryl ether; The POE-POP alkyl ethers such as POE (20) POP (4) cetyl ether; The polyoxyethylene polyoxypropylene block copolymers such as POE (196) POP (67) glycol (poloxamer188, pluronic (Pluronic) F127), POE (200) POP (70) glycol; The average addition molal quantity of the ethylene oxides such as polyoxyethylene castor oil 20, polyoxyethylene castor oil 35, polyoxyethylene castor oil 40, polyoxyethylene castor oil 50, polyoxyethylene castor oil 60 is the polyoxyethylene castor oil etc. of more than 20.It should be noted that, in above-mentioned illustrative compound, the numeral in bracket is addition molal quantity.
In addition, as can the compounding amphoteric surfactant to aqueous ophthalmic compositions of the present invention, alkyl diamino ethyl glycines or its salt (such as hydrochlorate etc.) etc. can specifically be exemplified.
In addition, as can the compounding cationic surfactant to aqueous ophthalmic compositions of the present invention, specifically benzalkonium chloride, benzethonium chloride etc. can be exemplified.
In addition, as can the compounding anionic surfactant to aqueous ophthalmic compositions of the present invention, alkylbenzenesulfonate, alkyl sulfate, laureth sulfate, aliphatic alpha-sulfo methyl ester, alpha-olefin sulfonic acid etc. can specifically be exemplified.
Be preferably nonionic surfactant, more preferably the average addition molal quantity of POE sorbitan fatty acid ester, POE castor oil hydrogenated, POEPOP block copolymer, ethylene oxide is the polyoxyethylene castor oil of more than 20, is particularly preferably polysorbate80, HCO60, poloxamer188, polyoxyethylene castor oil 35.
In aqueous ophthalmic compositions of the present invention, the surfactant beyond above-mentioned (A) composition can be used alone one, also can be used in combination.
In aqueous ophthalmic compositions of the present invention during compounding above-mentioned surfactant, about it containing proportional, can according to the kind of the kind of this surfactant, other compounding ingredients, the suitably setting such as dosage form containing proportional, this aqueous ophthalmic compositions.As surfactant containing a proportional example, relative to the total amount of aqueous ophthalmic compositions, the total amount that can exemplify the surfactant beyond (A) composition is 0.001 ~ 3w/v%, is preferably 0.01 ~ 2w/v%, is more preferably 0.05 ~ 1w/v%, more preferably 0.1 ~ 1w/v%.
Aqueous ophthalmic compositions of the present invention is preferably further containing buffer agent.Thereby, it is possible to the pH of adjustable aqueous ophthalmic compositions of the present invention.As can the compounding buffer agent to aqueous ophthalmic compositions of the present invention, as long as pharmaceutically, pharmacologically (in pharmacy) or the upper material allowed of physiology, be then not particularly limited.As an example of these buffer agents, borate buffer, phosphoric acid buffer agent, carbonate buffer, citric acid buffer agent, acetate buffer agent, aspartic acid, aspartate etc. can be listed.These buffer agents also can combinationally use.As borate buffer, boric acid or the borate such as alkali metal borate salt, boric acid base earth metal salt can be listed.As phosphoric acid buffer agent, the phosphate such as phosphoric acid or phosphoric acid alkali metal salt, alkali metal salts can be listed.Carbonic acid or the carbonate such as alkali metal carbonate salt, carbonic acid alkali earth metal salt can be listed as carbonate buffer.As citric acid buffer agent, citric acid or alkali metal citrates, citric acid alkali earth metal salt etc. can be listed.In addition, as borate buffer or phosphoric acid buffer agent, borate or phosphatic water and thing also can be used.As example more specifically, as borate buffer, boric acid or its salt (sodium borate, dipotassium tetraborate, potassium metaborate, ammonium borate, Borax etc.) can be exemplified; As phosphoric acid buffer agent, phosphoric acid or its salt (sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, tertiary sodium phosphate, dipotassium hydrogen phosphate, calcium monohydrogenphosphate, dalcium biphosphate etc.) can be exemplified; As carbonate buffer, carbonic acid or its salt (sodium bicarbonate, sodium carbonate, ammonium carbonate, potassium carbonate, calcium carbonate, potassium bicarbonate, magnesium carbonate etc.) can be exemplified; As citric acid buffer agent, citric acid or its salt (sodium citrate, potassium citrate, calcium citrate, monobasic sodium citrate, disodium citrate etc.) can be exemplified; As acetate buffer agent, acetic acid or its salt (ammonium acetate, potassium acetate, calcium acetate, sodium acetate etc.) can be exemplified; Aspartic acid or its salt (NaAsp, magnesium aspartate, potassium aspartate etc.) etc.In these buffer agents, preferred boric acid buffer agent (especially the combination of boric acid and Borax).
When in aqueous ophthalmic compositions of the present invention during compounding buffer agent, proportional for containing of this buffer agent, according to the kind of the kind of used buffer agent, other compounding ingredients, different from the dosage form etc. of proportional, this aqueous ophthalmic compositions, cannot lump together, such as, the total amount relative to this aqueous ophthalmic compositions can be exemplified, the ratio that the total amount of this buffer agent reaches 0.01 ~ 10w/v%, preferably reaches 0.05 ~ 5w/v%, more preferably reaches 0.1 ~ 2.5w/v%, preferably reaches 0.1 ~ 1w/v% further.
In addition, aqueous ophthalmic compositions of the present invention can also contain isotonic agent further.As can the compounding isotonic agent to aqueous ophthalmic compositions of the present invention, as long as pharmaceutically, pharmacologically (in pharmacy) or the upper material allowed of physiology, be then not particularly limited.As the object lesson of such isotonic agent, include, for example out sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, sodium sulfite, sodium sulfite, potassium chloride, calcium chloride, sodium chloride, magnesium chloride, potassium acetate, sodium acetate, sodium bicarbonate, sodium carbonate, sodium thiosulfate, magnesium sulfate, glycerol, propylene glycol etc.In these isotonic agents, preferably glycerine, propylene glycol, sodium chloride, potassium chloride, calcium chloride and magnesium chloride can be listed, preferably sodium chloride or glycerol can be listed further, particularly preferably sodium chloride can be listed.These isotonic agents can be used alone one, also can be used in combination arbitrarily.
When in aqueous ophthalmic compositions of the present invention during compounding isotonic agent, for this isotonic agent containing for proportional, different according to the kind etc. of the isotonic agent used, cannot lump together, such as, the total amount relative to aqueous ophthalmic compositions can be exemplified, the ratio that the total amount of this isotonic agent reaches 0.01 ~ 10w/v%, preferably reaches 0.05 ~ 5w/v%, preferably reaches 0.1 ~ 3w/v% further.
For the pH of aqueous ophthalmic compositions of the present invention, as long as in the scope that pharmaceutically, pharmacologically (in pharmacy) or physiology above allow, be then not particularly limited.As an example of the pH of aqueous ophthalmic compositions of the present invention, it enumerates 4.0 ~ 9.5, preferably 5.0 ~ 9.0, more preferably 6.2 ~ 8.5, further preferably 6.5 ~ 8 scope, particularly preferred example according to appointment 6.5 ~ 7.5.
In addition, for the osmotic pressure of aqueous ophthalmic compositions of the present invention, as long as in organism allowable range, be then not particularly limited.As an example of the osmotic pressure ratio of aqueous ophthalmic compositions of the present invention, be preferably 0.6 ~ 3.0, particularly preferably the scope of 0.7 ~ 2.0 preferably 0.5 ~ 5.0, further.The adjustment of osmotic pressure can use inorganic salt, polyhydric alcohol, sugar alcohol, sugar etc., utilizes method known in this technical field to carry out.According to the 15 edition revision Pharmacopeia of Japan, osmotic pressure is than being the osmotic pressure of sample and the ratio of 286mOsm (osmotic pressure of 0.9w/v% sodium-chloride water solution), and the osmometry (cryoscopic method) that osmotic pressure is recorded with Pharmacopeia of Japan is with reference to measuring.In addition, osmotic pressure is dry sodium chloride (reagent of Pharmacopeia of Japan standard) after 40 ~ 50 minutes at 500 ~ 650 DEG C than mensuration titer (0.9w/v% sodium-chloride water solution), natural cooling in exsiccator (silica gel), accurate weighing 0.900g wherein, is dissolved in purified water and is correctly mixed with 100mL or uses commercially available osmotic pressure than mensuration titer (0.9w/v% sodium-chloride water solution).
As long as aqueous ophthalmic compositions of the present invention can play effect of the present invention, except mentioned component, also can by various pharmacological component and/or physiologically active ingredient independent or appropriately combined and contain in right amount.This composition is not particularly limited, and such as, can exemplify and generally admit standard version (supervision of medicine thing examination research association) the middle ophthalmic the effective elements of the medicine recorded in 2000 with pharmaceuticals manufacture (import).Specifically, as the composition used in ophthalmic remedy, following composition can be listed.
Hydryllin: such as, iproheptine, diphhydramine hydrochloride, chlorphenamine maleate, ketotifen fumarate, Pemirolast Potassiu etc.
Decongestant: such as, hydrochloric acid tetrahydrozoline (tetryzoline), sulphuric acid naphazoline, sulphuric acid naphazoline, adrenalin hydrochloride, ephedrine hydrochloride, mephedrine etc.
Antibacterial: such as, cetyl pyridinium, benzalkonium chloride, benzethonium chloride, chlorhexidine hydrochloride, chlorhexidine gluconate, polyhexamethylene biguanidine hydrochloride etc.
Vitamin: such as, Flavin Adenin Dinucleotide Sodium, vitamin B12, acetic acid retinol, vitamin A palmitate, pyridoxine hydrochloride, pantothenylol, calcium pantothenate, tocopherol acetate etc.
Aminoacid: such as, potassium aspartate, magnesium aspartate etc.
Antiinflammatory: such as, glycyrrhizic acid dipotassium, pranoprofen, allantoin, Sodium Azulenesulfonate, guaiazulene (guaiazulene), berberine hydrochloride, berberine sulfate, lysozyme chloride, Radix Glycyrrhizae etc.
Other: such as, sodium cromoglicate, sodium chondroitin sulfate, hyaluronate sodium, Sulfamethoxazole, Sulfamethoxazole sodium etc.
In addition, in aqueous ophthalmic compositions of the present invention, as long as playing in the scope of this effect, according to its purposes, dosage form etc., conventionally suitably several additives can also be selected, and with one or more, containing appropriate amount.As these additives, such as, the various additives recorded in pharmaceuticals additive topical reference book 2007 (writing of Japanese pharmaceutical product additive association) can be exemplified.Composition representatively, can list following additive.
Carrier: such as, the aqueous carrier such as water, aquiferous ethanol.
Sugar: such as, cyclodextrin etc.
Sugar alcohol: such as, xylitol, sorbitol, mannitol etc.These compounds can be any one in d body, l body or dl body.
Antiseptic, antibacterial or antibacterial: such as, hydrochloric acid alkyl diamino ethyl glycines, sodium benzoate, ethanol, benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, methaform, sorbic acid, potassium sorbate, sodium dehydroacetate, methyl parahydroxybenzoate, ethylparaben, propyl p-hydroxybenzoate, butyl p-hydroxybenzoate, oxyquinoline sulfate, phenethanol, benzyl alcohol, Glokill (trade name, Rhodia company) etc.
Aqueous ophthalmic compositions of the present invention by adding above-mentioned (A) composition of aequum and (B) composition and other compounding ingredients as required and making it reach desired concn and prepare in carrier.Such as, eye drop, contact lens are releived liquid, collyrium or contact lens care agent, by using purified water make mentioned component dissolve or suspend, and be adjusted to regulation pH and osmotic pressure, carry out sterilization treatment by filtration sterilization etc. and prepare.For the dissolving of the dissolving of above-mentioned (A) and (B) composition and the high composition of other hydrophobicity, the composition can also with surfactant etc. in advance with solubilization mixes, stirs, add purified water further again, make it dissolve or suspend.
In the present invention, as the manufacture method of aqueous ophthalmic compositions, provide the method comprised the steps: the average addition molal quantity adding (A) ethylene oxide in the carrier comprising water is polyoxyethylene castor oil and (B) terpenoid of 2 ~ 12.
Aqueous ophthalmic compositions of the present invention refers to, relative to the total amount of this aqueous ophthalmic compositions, water containing proportional be the ophthalmic composition of more than 85w/v%.In this aqueous ophthalmic compositions, water containing being proportionally preferably more than 90w/v%, being more preferably more than 92w/v%, more preferably more than 95w/v%, being particularly preferably more than 97w/v%.As the water used in aqueous ophthalmic compositions of the present invention, as long as use pharmaceutically, the pharmacologically upper water allowed of (in pharmacy) or physiology, distilled water, light water (water), purified water, sterilizing purified water, water for injection, distilled water for injection etc. can be exemplified as such glassware for drinking water body.In addition, for the dosage form of the aqueous ophthalmic compositions in the present invention, as long as the operable dosage form of field of ophthalmology is then not particularly limited, preferably aqueous.Their definition is according to the 15 edition revision Pharmacopeia of Japan.
As the object lesson of aqueous ophthalmic compositions of the present invention, eye drop (also known as eye drop or put drops in one's eyes) can be listed [wherein, the eye drop that eye drop can drip when comprising contact lens], collyrium (also known as collyrium or eyewash) [wherein, the collyrium of eye can be washed] when collyrium comprises contact lens, contact lens is releived liquid, contact lens nursing products (contact lens disinfection agent, contact lens preservative agent, contact lens abluent, contact lens cleaning preservative agent, contact lens sterilization/preservation/abluent (contact lens multifunctional solution)) etc.The antifoaming speed of aqueous ophthalmic compositions of the present invention improves, and during use, the deviation of dropping liquid amount is little, is therefore particularly useful for the few eye drop of use amount, contact lens releives liquid.Particularly preferably eye drop.
In addition, aqueous ophthalmic compositions of the present invention improves preservation effect, therefore there is excellent antisepsis, and, due to its suppress the concentration of terpenoid through time the effect that reduces excellent, be applicable to aqueous ophthalmic combination, the i.e. product of multiple dose type once the rear reused aqueous ophthalmic compositions in Kaifeng, this aqueous ophthalmic compositions can stablize more than preservation a few days or several weeks.
As the container of storage aqueous ophthalmic compositions of the present invention, can use the container used usually used as the container of storage aqueous ophthalmic compositions, can be glass system, also can be plastics system.When using plastic production for receiving the container of aqueous ophthalmic compositions of the present invention, composition material for these plastic containers is not particularly limited, such as, PEN, polyarylate, polyethylene terephthalate, polypropylene, polyethylene, wantonly a kind of polyimides, their copolymer or mixture of more than two kinds can be listed.In addition, as above-mentioned copolymer, can list with 2, wantonly a kind of 6-glycol naphthalendicarboxylate, arylate units, polyethylene terephthalate unit, propylene units, ethylene unit, acid imide unit is main body, and containing other polyester unit, the copolymer of acid imide unit.In addition, when recording such as polyethylene terephthalate container in the present invention, refer to the weight of the composition material entirety relative to container, polyethylene terephthalate accounts for more than 50w/w%.
In addition, in these containers, polyethylene terephthalate container is the container of durability and cost aspect excellence, but the concentration sometimes observing terpenoid when being accommodated in polyethylene terephthalate container through time reduce.Even if aqueous ophthalmic compositions of the present invention is accommodated in polyethylene terephthalate container, due to its can by and with specific polyoxyethylene castor oil and terpenoid suppress the concentration of terpenoid through time reduce, therefore can effectively use polyethylene terephthalate container.Particularly, even contain more than polyethylene terephthalate 75w/w% relative to the weight of the composition material entirety of container, especially contain the high container of the polyethylene terephthalate containing ratio of more than 95w/w%, the concentration that also can not produce terpenoid through time reduce, can effectively use.
In addition, even if outpour a mouthful peripheral part for the container such as the nozzle that possesses of container of storage aqueous ophthalmic compositions of the present invention, its structure, composition material etc. are also not particularly limited.For the structure that the containers such as nozzle outpour mouthful peripheral part, mouth (such as nozzle) is outpoured as long as the structure that usually adopts as ophthalmic composition container (such as eye drop container), can be one-body molded with container body, also can distinguish molding with container body.For the structural material outpouring mouthful peripheral part or outpour mouth (such as nozzle), the structural material identical with the structural material of above-mentioned plastic containers can be exemplified.
Particularly from flexibility, cost aspect and/or from the viewpoint of inhibition improving further dropping liquid amount deviation, preferably outpour mouth containing polyethylene or polypropylene as structural material.But, when making nozzle with these materials, the concentration that terpenoid easily occurs through time reduce.Consider that one of its reason is that these materials are easy to adsorb terpenoid.According to aqueous ophthalmic compositions of the present invention, even if being accommodated in the structural material outpouring mouth contains in polyethylene or polyacrylic container, also by and with specific polyoxyethylene castor oil and terpenoid suppress the concentration of terpenoid through time reduce.Therefore can effectively use the structural material outpouring mouth to contain polyethylene or polyacrylic container.
Poly kind can be enumerated as high density polyethylene (HDPE), Low Density Polyethylene etc., wherein, preferably outpours mouth containing Low Density Polyethylene as structural material.In addition, as outpouring mouth, nozzle used in preferred eye drop container.
The preferred compositions of mouthful peripheral part is outpoured as the container and container of receiving aqueous ophthalmic compositions of the present invention, it is the combination that polyethylene terephthalate container and polyethylene container outpour mouthful peripheral part, the more preferably combination of polyethylene terephthalate eye drip container and polyethylene nozzle, be particularly preferably the combination of polyethylene terephthalate eye drip container and Low Density Polyethylene nozzle, this type of combination can play the inhibition to dropping liquid amount deviation of the present invention well.
Aqueous ophthalmic compositions of the present invention have suppress terpenoid concentration through time reduce effect, even if therefore use there is the container that the container body portion of above-mentioned material and said vesse outpour mouthful peripheral part, the refrigerant sense that also can terpenoid be kept steadily in the long term to bring, also can play the effect that compounding specific polyoxyethylene castor oil and terpenoid simultaneously bring steadily in the long term.
Aqueous ophthalmic compositions of the present invention can make antifoaming speed improve, and the deviation of dropping liquid amount when suppressing to use, and when making each eye drip, use amount remains constant, is therefore particularly preferably used as the eye drop containing pharmacological component and/or physiologically active ingredient.The purposes of these eye drop can list antipruritic eye drop, anti-asthenopia eye drop etc.
In addition, the present invention, from the view point of other, provides a kind of average addition molal quantity of (A) ethylene oxide to be the polyoxyethylene castor oil of 2 ~ 12 and the purposes for the manufacture of aqueous ophthalmic compositions of (B) terpenoid.
And then, the present invention from other viewpoint, the average addition molal quantity also providing one to comprise (A) ethylene oxide be the polyoxyethylene castor oil of 2 ~ 12 and the compositions of (B) terpenoid, as the purposes of aqueous ophthalmic compositions.
And then the present invention, from other viewpoint, provides a kind of compositions, it is used as aqueous ophthalmic compositions, and the average addition molal quantity comprising (A) ethylene oxide is polyoxyethylene castor oil and (B) terpenoid of 2 ~ 12.
The method of the deviation of dropping liquid amount [when 2. the improving the method for antifoaming speed and suppress to use]
As mentioned above, pass through in aqueous ophthalmic compositions of the present invention and use (A) and (B) composition, the antifoaming speed of aqueous ophthalmic compositions can be improved, the deviation of dropping liquid amount when suppressing to use.
Therefore, the present invention is further from other viewpoint, there is provided a kind of method improving the antifoaming speed of aqueous ophthalmic compositions, it comprises: in this aqueous ophthalmic compositions, the average addition molal quantity of compounding (A) aqueous ethylene oxide is the polyoxyethylene castor oil of 2 ~ 12 and (B) terpenoid.
In addition, the invention provides a kind of method improving the antifoaming speed of aqueous ophthalmic compositions, it comprises: to being compounding (B) terpenoid in the aqueous ophthalmic compositions of the polyoxyethylene castor oil of 2 ~ 12 containing the average addition molal quantity of (A) ethylene oxide.
In addition, the invention provides a kind of method suppressing the aqueous ophthalmic compositions deviation of dropping liquid amount in use, it comprises: the average addition molal quantity of compounding in hydrotropism's ophthalmic composition (A) ethylene oxide is the polyoxyethylene castor oil of 2 ~ 12 and (B) terpenoid.
In addition, the invention provides a kind of method improving the antifoaming speed of aqueous ophthalmic compositions and the method suppressing this aqueous ophthalmic compositions deviation of dropping liquid amount in use, it comprises: in the aqueous ophthalmic compositions containing the surfactant beyond (A) composition, the average addition molal quantity of compounding (A) ethylene oxide is the polyoxyethylene castor oil of 2 ~ 12 and (B) terpenoid.
The kind of (A) and (B) composition that these methods are used, they containing proportional (or compounding ratio), their ratio, the kind of other compounding composition or identical with above-mentioned " 1. aqueous ophthalmic compositions " containing proportional (or compounding ratio), the dosage form of aqueous ophthalmic compositions, the kind of container or combination, implementation method etc.
Wherein, these methods are preferably applicable to the situation that aqueous ophthalmic compositions is eye drop, contact lens releives liquid.
[3. strengthening the method for preservation effect]
In addition, as mentioned above, by also can strengthen the preservation effect of aqueous ophthalmic compositions with (A) and (B) composition.
Therefore, the present invention is further from other viewpoint, there is provided a kind of method strengthening the preservation effect of aqueous ophthalmic compositions, it comprises: the average addition molal quantity of compounding in hydrotropism's ophthalmic composition (A) aqueous ethylene oxide is polyoxyethylene castor oil and (B) terpenoid of 2 ~ 12.
In addition, the invention provides a kind of method strengthening aqueous ophthalmic compositions preservation effect, it comprises: to being the polyoxyethylene castor oil of 2 ~ 12 containing the average addition molal quantity of compounding ethylene oxide in the aqueous ophthalmic compositions of (B) terpenoid.
The kind of (A) and (B) composition used in these methods, they containing proportional (or compounding ratio), their ratio, the kind of other compounding composition or identical with above-mentioned " 1. aqueous ophthalmic compositions " containing proportional (or compounding ratio), the dosage form of aqueous ophthalmic compositions, the kind of container or combination, implementation method etc.
Wherein, these methods are applicable to aqueous ophthalmic compositions, i.e. product that aqueous ophthalmic compositions is multiple dose type once reused aqueous ophthalmic compositions behind Kaifeng, and these aqueous ophthalmic compositionss can be enumerated as multiple dose type eye drop, multiple dose type collyrium, multiple dose type contact lens releive liquid, multiple dose type contact lens nursing products.
[being 4. separated suppressing method]
In addition, as mentioned above, by and the separation of the refractory components such as (A) composition in aqueous ophthalmic compositions or (B) composition can be suppressed with (A) and (B) composition, make preparation physical property remain stable.
Therefore, the present invention is further from other viewpoint, there is provided a kind of method suppressing the separation of aqueous ophthalmic compositions, it comprises: the average addition molal quantity of compounding in hydrotropism's ophthalmic composition (A) aqueous ethylene oxide is polyoxyethylene castor oil and (B) terpenoid of 2 ~ 12.In addition, the invention provides a kind of method suppressing the separation of aqueous ophthalmic compositions, it comprises: to being compounding (B) terpenoid in the aqueous ophthalmic compositions of the polyoxyethylene castor oil of 2 ~ 12 containing the average addition molal quantity of (A) ethylene oxide.In addition, the present invention also provides a kind of method suppressing the separation of aqueous ophthalmic compositions, and it comprises: to being the polyoxyethylene castor oil of 2 ~ 12 containing the average addition molal quantity of compounding ethylene oxide in the aqueous ophthalmic compositions of (B) terpenoid.
The kind of (A) and (B) composition that these methods are used, they containing proportional (or compounding ratio), their ratio, the kind of other compounding composition or identical with above-mentioned " 1. aqueous ophthalmic compositions " containing proportional (or compounding ratio), the dosage form of aqueous ophthalmic compositions, the kind of container or combination, implementation method etc.
[5. suppress terpenoid concentration through time reduce method]
In addition, as mentioned above, by and when the aqueous ophthalmic compositions containing mentioned component can be suppressed to receive in a reservoir with (A) and (B) composition, the concentration of its (B) composition through time reduce.Can infer, and during with (A) and (B) composition, (B) composition in this aqueous ophthalmic compositions is suppressed to container adsorption or from container volatilization etc.Therefore, can long term maintenance aqueous ophthalmic compositions refrigerant sense and can long term maintenance effect of the present invention.
Therefore, the present invention is from other viewpoint, the concentration of the terpenoid in the aqueous ophthalmic compositions providing a kind of suppression to be accommodated in container through time the method that reduces, it comprises: the average addition molal quantity of compounding in hydrotropism's ophthalmic composition (A) ethylene oxide is polyoxyethylene castor oil and (B) terpenoid of 2 ~ 12.
And then, the invention provides a kind of suppress the concentration of above-mentioned terpenoid through time reduce method, the container being accommodated with aqueous ophthalmic compositions is the polyethylene terephthalate container being provided with polyethylene nozzle.
In addition, the present invention is from other viewpoint, there is provided a kind of give aqueous ophthalmic compositions with the concentration of the terpenoid in this aqueous ophthalmic compositions that suppresses to be accommodated in container through time the method that reduces, it comprises: to being the polyoxyethylene castor oil of 2 ~ 12 containing the average addition molal quantity of compounding (A) ethylene oxide in the aqueous ophthalmic compositions of (B) terpenoid.
And then, the invention provides a kind of give aqueous ophthalmic compositions with the concentration of the terpenoid in this aqueous ophthalmic compositions that suppresses to be accommodated in container through time the method that reduces, the container of storage aqueous ophthalmic compositions is the polyethylene terephthalate container being provided with polyethylene nozzle.
The kind of (A) and (B) composition that these methods are used, they containing proportional (or compounding ratio), their ratio, the kind of other compounding composition or identical with above-mentioned " 1. aqueous ophthalmic compositions " containing proportional (or compounding ratio), the dosage form of aqueous ophthalmic compositions, the kind of container or combination, implementation method etc.
Wherein, these methods are preferably applicable to the situation that aqueous ophthalmic compositions is eye drop, contact lens releives liquid.
[the maintenance method of 6. refrigerant sense]
In addition, as mentioned above, by also using (A) and (B) composition in aqueous ophthalmic compositions, the refrigerant sense of aqueous ophthalmic compositions can be maintained.Therefore, it is possible to the refrigerant sense of aqueous ophthalmic compositions when maintaining eye drip etc.
Therefore, the present invention is further from other viewpoint, there is provided a kind of method maintaining the refrigerant sense of aqueous ophthalmic compositions, it comprises: the average addition molal quantity of compounding in hydrotropism's ophthalmic composition (A) ethylene oxide is polyoxyethylene castor oil and (B) terpenoid of 2 ~ 12.
The kind of (A) and (B) composition that these methods are used, their kind containing proportional (or compounding ratio), their ratio, other compounding composition, identical with above-mentioned " 1. aqueous ophthalmic compositions " containing proportional (or compounding ratio), the dosage form of aqueous ophthalmic compositions, the kind of container or combination, implementation method etc.
Wherein, these methods are preferably applicable to the situation that aqueous ophthalmic compositions is eye drop, contact lens releives liquid.
Embodiment
Below, explain the present invention according to embodiment, but the present invention is not limited to these embodiments.
[correlation test (1) of test example 1 antifoaming speed]
Conventionally prepare the aqueous ophthalmic compositions (embodiment 1-1, comparative example 1-1) of the composition shown in following table 1, use these, evaluate antifoaming speed.Specifically, the foaming of the aqueous ophthalmic compositions that the aqueous ophthalmic compositions containing various surfactant and those be with the addition of to terpenoid when vibrating and the antifoaming speed after certain hour are evaluated.
First, each aqueous ophthalmic compositions (comparative example 1-1, embodiment 1-1) shown in table 1 is prepared.It should be noted that, l-menthol is the product meeting the 15th edition revision Pharmacopeia of Japan specification, polyoxyethylene castor oil 10 is for meeting the product of the polyoxyethylene castor oil specification in pharmaceuticals additive specification 2003, and the average addition molal quantity of its ethylene oxide is 10.
Subsequently, fill each aqueous ophthalmic compositions 30mL respectively in the glass centrifuge tube of 50mL capacity, use RECIPAD SHAKER SR-2w (TAITEC), vibrate 1500 times.After vibration terminates, visual confirmation foam segment and aqueous solution part at once, measures the volume of foam segment.Then left standstill, measured the volume of its time dependent foam segment, according to foam completely disappearance required time evaluate antifoaming speed.Result merging is shown in table 1.
[table 1]
Unit (w/v%)
The volume of the foam segment measured immediately after stirring, embodiment 1-1 is identical with comparative example 1-1 degree.But after 1 minute, the volume reducing of the foam segment of embodiment 1-1 is to about 1/8th of comparative example 1-1.And foam is disappeared required time completely, as shown in table 1, relative to containing polyoxyethylene castor oil 10, do not need 165 minutes containing the aqueous ophthalmic compositions (comparative example 1-1) of terpenoid (menthol), just disappear completely in 15 minutes containing the foam of polyoxyethylene castor oil 10 with the aqueous ophthalmic compositions (embodiment 1-1) of terpenoid (menthol) simultaneously.
[correlation test (2) of test example 2 antifoaming speed]
More solito preparation is as shown in table 2, the aqueous ophthalmic compositions (embodiment 1-2 and comparative example 1-2 ~ 1-4) containing the surfactant (polysorbate80) beyond (A) composition.It should be noted that, l-menthol and polysorbate80 are the product meeting the 15th edition revision Pharmacopeia of Japan specification, polyoxyethylene castor oil 10 and polyoxyethylene castor oil 35 are for meeting the product of the polyoxyethylene castor oil specification in pharmaceuticals additive specification 2003, and the average addition molal quantity of its ethylene oxide is respectively 10 and 35.
Use these aqueous ophthalmic compositionss, according to the method identical with test example 1, implement antifoaming speed correlation test.In addition, antifoaming speed is evaluated according to initial foam required time that reduces by half.Result merging is shown in table 2.
[table 2]
Unit (w/v%)
The volume of the foam segment measured immediately after the stirring of embodiment 1-2 and comparative example 1-2 ~ 1-4, the volume of the foam segment of comparative example 1-2 about has more about 30% than other three preparations, but the foam segment volume degree of comparative example 1-3,1-4 and embodiment 1-2 is identical.But, foam is reduced by half the required time, as shown in table 2, need 120 minutes containing polyoxyethylene castor oil 10 and the aqueous ophthalmic compositions (comparative example 1-2) of polysorbate80, the aqueous ophthalmic compositions (comparative example 1-3) containing menthol and polysorbate80 needs 450 minutes.
On the other hand, the aqueous ophthalmic compositions (embodiment 1-2) containing polyoxyethylene castor oil 10, menthol and polysorbate80 only needs 50 minutes, and its foam just reduces by half.And use polyoxyethylene castor oil 35 to replace the aqueous ophthalmic compositions of polyoxyethylene castor oil 10 (comparative example 1-4) to need 380 minutes.
From above result, by also with polyoxyethylene castor oil 10 and terpenoid, the speed of the lather collapse produced because of the existence of other surfactant (such as polysorbate80) can be significantly improved.It should be noted that, when using polyoxyethylene castor oil 35 to replace polyoxyethylene castor oil 10, this effect is very low.
[correlation test (3) of test example 3 antifoaming speed]
Conventionally prepare as shown in table 3 ~ 5, each aqueous ophthalmic compositions (embodiment 1-3 ~ 1-12 and comparative example 1-5 ~ 1-6) containing the surfactant (polysorbate80) beyond (A) composition.It should be noted that, l-menthol, eucalyptus oil and polysorbate80 are the product of satisfied 15th edition revision Pharmacopeia of Japan specification, and geraniol is the product of the specification meeting pharmaceuticals additive specification 2003.Polyoxyethylene castor oil 3 is for meeting the product of the specification of the polyoxyethylene castor oil in pharmaceuticals additive specification 2003, and the average addition molal quantity of its ethylene oxide is 3.
Use these aqueous ophthalmic compositionss, according to the method identical with test example 1, implement antifoaming speed correlation test.In addition, according to the Time evaluation antifoaming speed that initial foam reduces by half required.Result merging is shown in table 3 ~ 5.
[table 3]
Unit (w/v%)
[table 4]
Unit (w/v%)
[table 5]
Unit (w/v%)
From table 3 and table 4, compared with the aqueous ophthalmic compositions only containing polyoxyethylene castor oil 3, obviously shortening (comparative example 1-5 and embodiment 1-3 ~ 1-10) to steeping the required time that reduces by half of the aqueous ophthalmic compositions containing polyoxyethylene castor oil 3 and containing l-menthol, geraniol or eucalyptus oil.
Similarly, as shown in Table 5, compared with the aqueous ophthalmic compositions only containing polyoxyethylene castor oil 10, containing polyoxyethylene castor oil 10, and the extremely bubble containing the aqueous ophthalmic compositions of l-menthol or geraniol reduces by half, the required time obviously shortens (comparative example 1-6 and embodiment 1-11,1-12).
[correlation test (4) of test example 4 antifoaming speed]
Conventionally prepare as shown in table 6, containing the surfactant (polyoxyethylene castor oil 35) beyond (A) composition each aqueous ophthalmic compositions (embodiment 1-13,1-14 and comparative example 1-7,1-8).It should be noted that, during preparation aqueous ophthalmic compositions, need to add a certain amount of Borax, make the pH of aqueous ophthalmic compositions be 7.In addition, d-Camphora is the product meeting the 15th edition revision Pharmacopeia of Japan specification, and d-Borneolum Syntheticum is the product meeting pharmaceuticals additive specification 2003 specification.Polyoxyethylene castor oil 3, polyoxyethylene castor oil 10 and polyoxyethylene castor oil 35 are for meeting the product of the polyoxyethylene castor oil specification in pharmaceuticals additive specification 2003, and the average addition molal quantity of its ethylene oxide is respectively 3,10 and 35.
Use these aqueous ophthalmic compositionss, it is filled liquid measure and is decided to be 20mL, and all the other are all identical with test example 1 method, implements antifoaming speed correlation test.In addition, extremely the Time evaluation antifoaming speed reducing by half required is steeped according to initial.Result merging is shown in table 6.
[table 6]
Unit (w/v%)
To steeping, the required time that reduces by half is as shown in table 6, need 300 minutes containing polyoxyethylene castor oil 3 and the prescription (comparative example 1-7) of polyoxyethylene castor oil 35, need 390 points containing polyoxyethylene castor oil 10 and the aqueous ophthalmic compositions (comparative example 1-8) of polyoxyethylene castor oil 35.
On the other hand, aqueous ophthalmic compositions (embodiment 1-13) containing polyoxyethylene castor oil 3, polyoxyethylene castor oil 35 and Camphora only needs 160 minutes foams just to reduce by half, and the aqueous ophthalmic compositions (embodiment 1-14) containing polyoxyethylene castor oil 10, polyoxyethylene castor oil 35 and Borneolum Syntheticum only needs 100 minutes foams just to reduce by half.
[correlation test (5) of test example 5 antifoaming speed]
Conventionally prepare as shown in table 7, containing the surfactant (polysorbate80) beyond (A) composition each aqueous ophthalmic compositions (embodiment 1-15 ~ 1-17 and comparative example 1-9,1-10).It should be noted that, l-menthol and polysorbate80 are the product meeting the 15th edition revision Pharmacopeia of Japan specification, polyoxyethylene castor oil 3 and polyoxyethylene castor oil 10 are for meeting the product of the polyoxyethylene castor oil specification in pharmaceuticals additive specification 2003, and the average addition molal quantity of its ethylene oxide is respectively 3 and 10.
Use these aqueous ophthalmic compositionss, according to the method identical with test example 1, implement antifoaming speed correlation test.In addition, according to the Time evaluation antifoaming speed that initial foam reduces by half required.Result merging is shown in table 7.
[table 7]
Unit (w/v%)
As shown in Table 7, compared with only containing the aqueous ophthalmic compositions of polyoxyethylene castor oil 3 or polyoxyethylene castor oil 10, significantly shortening (comparative example 1-9,1-10 and embodiment 1-15 ~ 1-17) to steeping the required time that reduces by half of the aqueous ophthalmic compositions containing polyoxyethylene castor oil 3 or polyoxyethylene castor oil 10 and containing l-menthol.
[correlation test (6) of test example 6 antifoaming speed]
Conventionally be formulated as follows state shown in table 8 and by polyoxyethylene castor oil 3 and the polyoxyethylene castor oil 10 each aqueous ophthalmic compositions (embodiment 1-18,1-19) as (A) composition and containing the surfactant (polysorbate80) beyond (A) composition.It should be noted that, l-menthol and polysorbate80 are the product meeting the 15th edition revision Pharmacopeia of Japan specification, polyoxyethylene castor oil 3 and polyoxyethylene castor oil 10 are for meeting the product of the polyoxyethylene castor oil specification in pharmaceuticals additive specification 2003, and the average addition molal quantity of its ethylene oxide is respectively 3 and 10.
Use these aqueous ophthalmic compositionss, according to the method identical with test example 1, implement antifoaming speed correlation test.In addition, extremely the Time evaluation antifoaming speed reducing by half required is steeped according to initial.Result as described in Table 8.
[table 8]
Unit (w/v%)
Embodiment 1-18 Embodiment 1-19
Polyoxyethylene castor oil 3 0.1 0.05
Polyoxyethylene castor oil 10 0.1 0.1
L-menthol 0.02 0.01
Polysorbate80 0.2 0.2
Boric acid 0.5 0.5
Borax 0.02 0.02
Purified water (mL) Surplus Surplus
pH 7 7
Time (minute) required to bubble reduces by half 25 50
As shown in Table 8, by and with polyoxyethylene castor oil 3 and polyoxyethylene castor oil 10, simultaneously and with l-menthol, significantly foreshorten to bubble and reduce by half the required time.
Can be clear and definite according to above result, even be also the aqueous ophthalmic compositions of the polyoxyethylene castor oil of 2 ~ 12 with the average addition molal quantity of ethylene oxide, contain by making it disappearance speed that terpenoid also can significantly improve produced foam.
[correlation test of test example 7 antifoaming speed and dropping liquid amount]
Conventionally prepare the aqueous ophthalmic compositions (embodiment 2-1 ~ 2-3 and comparative example 2-1,2-2) shown in following table 9, carry out the relevant evaluation of antifoaming speed and dropping liquid amount.It should be noted that, l-menthol and polysorbate80 are the product meeting the 15th edition revision Pharmacopeia of Japan specification, and geraniol and HCO60 are the product of the specification meeting pharmaceuticals additive specification 2003.Polyoxyethylene castor oil 10 is for meeting the product of the specification of the polyoxyethylene castor oil in pharmaceuticals additive specification 2003, and the average addition molal quantity of its ethylene oxide is 10.
First, fill aqueous ophthalmic compositions 6.5mL respectively to each in the polyethylene terephthalate eye drip container of 13mL capacity, assembling Low Density Polyethylene nozzle, as eye drop.Separately filter paper is loaded in mensuration container, seal, measure the gross weight (initial value) of filter paper and mensuration container.The angle of the nozzle of eye drip container is set to level (container is for horizontal), in mensuration container, drips 1 dripping property ophthalmic composition.Subsequently, mensuration container is sealed.Measure the filter paper after imbitition and the gross weight of mensuration container, deduct initial value, measure the dropping liquid amount (weight) of 1.Repeatedly measure 10 times, the deviation between recycling 10 calculates SD value (the SD value of the front dropping liquid amount of vibration).
After these eye drip containers of upper and lower thermal agitation 20 times, leave standstill 10 minutes.Afterwards, use above-mentioned same procedure, measure the dropping liquid amount (weight) of 1, and utilize the deviation between 10 to calculate SD value (the SD value of the rear dropping liquid amount of vibration).
According to the rate of change of the SD value before and after following formulae discovery vibration, calculate the rate of change (doubly) of deviation.Result merging is shown in table 9.
SD value before SD value/vibration after rate of change (the doubly)=vibration of deviation
[table 9]
Unit (w/v%)
About the SD value of dropping liquid amount after vibration, comparative example 2-1 is about about 2 times before vibration, and embodiment 2-1 is about 1.3 times before vibration.That is, compared with comparative example 2-1, the deviation variation rate of embodiment 2-1 is significantly little, and the deviation of the dropping liquid amount after its vibration is obviously suppressed.In addition, comparative example 2-2 and embodiment 2-2,2-3 more also demonstrate identical tendency.
Can be clear and definite by above result, even and if used the aqueous ophthalmic compositions of the present invention of polyoxyethylene castor oil 10 and terpenoid because of circulation or the carrying etc. of user cause preparation to bubble time, dropping liquid amount during use also can be made to maintain and to stablize.
[test example 8 is separated inhibition test]
(embodiment 3-1 and comparative example 3-1, visual valuation is with or without occurring segregation phenomenon conventionally to prepare the aqueous ophthalmic compositions shown in following table 10.It should be noted that, l-menthol is the product meeting the 15th edition revision Pharmacopeia of Japan specification, polyoxyethylene castor oil 10 is for meeting the product of the polyoxyethylene castor oil specification in pharmaceuticals additive specification 2003, and the average addition molal quantity of its ethylene oxide is 10.Specifically, after the character of the aqueous ophthalmic compositions that visual confirmation has just been prepared, get each aqueous ophthalmic compositions 1mL, be packed in centrifuge tube, use centrifuge (MX-100TOMY), under 6000G centrifugal 3 minutes, again visual confirmation centrifugal after the character of aqueous ophthalmic compositions, to be separated the aqueous ophthalmic compositions that there is difference in specific gravity.Result merging is shown in table 10.
[table 10]
Unit (w/v%)
The character of each aqueous ophthalmic compositions of (before centrifugal) has just been prepared in visual confirmation, and it is uniform white opacity liquid.But find during character after visual confirmation each aqueous ophthalmic compositions is centrifugal, comparative example 3-1 is separated into clear aqueous solution part and infers is the white solid of polyoxyethylene castor oil 10.In addition, embodiment 3-1 after centrifugation, centrifugal before be identical white opacity liquid, have no precipitate, therefore confirm that its separation is suppressed, each composition in aqueous ophthalmic compositions still evenly exists.
Can be clear and definite according to above result, although the water solublity of polyoxyethylene castor oil 10 is lower, it is by lower l-menthol same with water solublity and use, unexpectedly becomes and is difficult to be separated in water solublity ophthalmic composition.
[test of test example 9 particle size determination]
Conventionally prepare the aqueous ophthalmic compositions (embodiment 3-2 and comparative example 3-2) shown in following table 11, use the particle diameter in particle size determination device (FPAR-1000 (large tomb electronics)) mensuration aqueous ophthalmic compositions.It should be noted that, l-menthol is the product meeting the 15th edition revision Pharmacopeia of Japan specification, and HCO60 is the product of the specification meeting pharmaceuticals additive specification 2003.Polyoxyethylene castor oil 10 is for meeting the product of the specification of the polyoxyethylene castor oil in pharmaceuticals additive specification 2003, and the average addition molal quantity of its ethylene oxide is 10.Result merging is shown in table 11.
Detailed measuring conditions is as follows.
Condition determination
Temperature 25 DEG C
ND value AUTO (10% or 25%)
Probe is concentrated to be used
Minute 180 seconds
Number of repetition 1 time
Dust cutting (dust cutting) 10 times (upper 10%, lower 1000%)
Light quantity adjusts
Best homodyne light quantity 30000cps
MAX50000cps
MIN10000cps
Analytical method
Marquardt (Marquardt) (Lambda1000, interation1000)
[table 11]
Unit (w/v%)
The mean diameter of comparative example 3-2 is about the mean diameter 1.4 times of embodiment 3-2.In this test, measure with the particle diameter of the micelle of the aqueous ophthalmic compositions making its dissolubility and be improved also added nonionic surfactant (HCO60) except polyoxyethylene castor oil 10.Consider that the little then micelle difficulty of particle diameter is assembled, difficult separation, therefore embodiment 3-2 separation more difficult than comparative example 3-2 can be said.
[concentration of test example 10 terpenoid through time the test that reduces]
Conventionally prepare the aqueous ophthalmic compositions (embodiment 4-1 and comparative example 4-1,4-2) shown in following table 12, be packed in the eye drip container that polyethylene terephthalate (following PET) makes, carried out the concentration change validation test of menthol.It should be noted that, l-menthol is the product meeting the 15th edition revision Pharmacopeia of Japan specification, and HCO60 is the product of the specification meeting pharmaceuticals additive specification 2003.Polyoxyethylene castor oil 10 and polyoxyethylene castor oil 35 are for meeting the product of the specification of the polyoxyethylene castor oil of pharmaceuticals additive specification 2003, and the average addition molal quantity of its ethylene oxide is 10 and 35.
First, fill each aqueous ophthalmic compositions 10mL (embodiment 4-1 and comparative example 4-1,4-2) respectively to each in the eye drip container of the PET of 10mL capacity, assembling Low Density Polyethylene Nozzle back seal.Equally, each aqueous ophthalmic compositions 10mL is filled, sealing respectively to each in the glass ampule pipe (glass container) of 10mL capacity.In addition, consider that the menthol in the aqueous ophthalmic compositions of enclosing in glass container adsorbs hardly, and the loss of menthol that volatilization etc. cause is also less, therefore with comparing.
By each sample at 60 DEG C, under the state leaving standstill 3 days (glass container upright, eye drip container stand upside down), carry out keeping, the concentration of the menthol subsequently in each aqueous ophthalmic compositions of use gas chromatography determination.For the aqueous ophthalmic compositions of same composition, use the concentration deducting menthol in eye drip container in the menthol concentration in glass container (contrast), calculate its loss amount relative to the menthol contrasted.Then, the menthol loss rate of the embodiment 4-1 when menthol loss amount of comparative example 4-1 being set to 100, comparative example 4-2 is calculated.Result merging is shown in table 12.
[table 12]
Unit (w/v%)
Compared with the aqueous ophthalmic compositions only using HCO60 as surfactant (comparative example 4-1), and with polyoxyethylene castor oil 10 and HCO60 as the aqueous ophthalmic compositions (embodiment 4-1) of surfactant when filling and be stored in eye drip container, menthol loss obviously reduces.In addition, use polyoxyethylene castor oil 35 replace the aqueous ophthalmic compositions of polyoxyethylene castor oil 10 (comparative example 4-2) when filling and be stored in eye drip container, its suppress menthol concentration through time reduce effect unlike use polyoxyethylene castor oil 10 embodiment 4-1 high.
[test example 11 preservation effect test (1)]
Conventionally prepare the aqueous ophthalmic compositions (embodiment 5-1 and comparative example 5-1 ~ 5-3) shown in following table 13, carry out the preservation effect test of each aqueous ophthalmic compositions.Be specially, Staphylococcusaureus (ATCC6538) be seeded in the surface of soybean casein digestion slant medium, cultivate 24 hours at 33 DEG C.Use inoculating loop sterilely to extract cultivation thalline, make it swim in appropriate sterile saline, preparation is about containing 1 × 10 5the antibacterial of the viable bacteria of CFU/mL swims liquid.The viable count of ， Fu Swam liquid is cultivated separately in addition, and measures.Then, respectively to each aqueous ophthalmic compositions 10mL after wadding warp filtration sterilization each in 15mLCORNIA conical pipe (PET).In this aqueous ophthalmic compositions, inoculate Staphylococcus aureus bacterium liquid (suspending in normal saline solution), make viable count (ultimate density) be about 103CFU/mL (3Log), fully stir and make sample.Sample is kept in Dark Place 3 days at 23 DEG C.After 3 days, the sample containing bacterium being mixed with the debita spissitudo for counting, carrying out the counting of bacterium according to membrane-filter procedure.More firm postvaccinal viable count and the viable count in the sample preserved after 3 days, calculate bacterium Shuo Minus on a small quantity as log reduction (Log Reduction).In addition, the cultivation for the bacterium counted is implemented 3 days at 33 DEG C.It should be noted that, l-menthol is the product of the specification meeting the 15th edition revision Pharmacopeia of Japan, and HCO60 is the product of the specification meeting pharmaceuticals additive specification 2003.Polyoxyethylene castor oil 10 and polyoxyethylene castor oil 35 are for meeting the product of the specification of the polyoxyethylene castor oil of pharmaceuticals additive specification 2003, and the average addition molal quantity of its ethylene oxide is 10 and 35.Result merging is shown in table 13.
[table 13]
Unit (w/v%)
In the only compounding comparative example 5-1 of menthol, almost have no the minimizing of bacterium.In addition, in the only compounding comparative example 5-2 of polyoxyethylene castor oil 10, bacterium decreases 1.6log.On the other hand, the compounding preservation effect having menthol and the embodiment 5-1 both polyoxyethylene castor oil 10 to have kill bacteria degree.Compounding polyoxyethylene castor oil 35 replaces in the comparative example 5-3 of polyoxyethylene castor oil 10, does not find so high preservation effect.
[test example 12 preservation effect test (2)]
More solito prepares the aqueous ophthalmic compositions (embodiment 5-2,5-3 and comparative example 5-4,5-5) shown in following table 14, use these aqueous ophthalmic compositionss, according to the method identical with test example 11, relatively the viable count of the firm postvaccinal viable count of Staphylococcus aureus and the sample of preservation after 7 days, calculates the Minus of bacterium number on a small quantity as Log reduction.In addition, the cultivation for the bacterium counted is implemented at 33 DEG C.It should be noted that, d-Camphora is the product of the specification meeting the 15th edition revision Pharmacopeia of Japan, and geraniol, HCO60 are the product of the specification meeting pharmaceuticals additive specification 2003.Polyoxyethylene castor oil 10 and polyoxyethylene castor oil 35 are for meeting the product of the specification of the polyoxyethylene castor oil of pharmaceuticals additive specification 2003, and the average addition molal quantity of its ethylene oxide is 10 and 35.Result merging is shown in table 14.
[table 14]
Unit (w/v%)
Comparative example 5-4 Embodiment 5-2 Comparative example 5-5 Embodiment 5-3
Polyoxyethylene castor oil 10 - 0.025 - 0.4
Polyoxyethylene castor oil 35 - - 0.4 -
HCO60 0.175 0.15 0.5 0.5
D-Camphora - - 0.05 0.05
Geraniol 0.003 0.003 - -
Boric acid 0.5 0.5 0.5 0.5
Borax 0.05 0.05 0.05 0.05
Sodium hydroxide In right amount In right amount In right amount In right amount
Hydrochloric acid In right amount In right amount In right amount In right amount
Purified water In right amount In right amount In right amount In right amount
pH 7.3 7.3 7.3 7.3
Log reduction 3.7 4.7 1.9 2.5
Can be clear and definite from table 14, compared with the only compounding comparative example 5-4 of geraniol, compounding have polyoxyethylene castor oil 10 obviously to reduce with the bacterium number of the embodiment 5-2 of geraniol, can confirm its high preservation effect.In addition, compare with the comparative example 5-5 of d-Camphora with compounding polyoxyethylene castor oil 35, compounding have the bacterium number of the embodiment 5-3 of polyoxyethylene castor oil 10 and d-Camphora obviously to reduce, and can confirm its high preservation effect.
Known above, be polyoxyethylene castor oil and terpenoid thus the high preservation effect shown Staphylococcus aureus of 2 ~ 12 by the average addition molal quantity containing ethylene oxide.
[test example 13 preservation effect test (3)]
Conventionally prepare the aqueous ophthalmic compositions (embodiment 5-4 and comparative example 5-6) shown in following table 15, use these aqueous ophthalmic compositionss, according to the method identical with test example 11, viable count in sample after more just having inoculated the viable count after Staphylococcus aureus and E.Coli and having preserved, calculates the Log reduction of bacterium number reduction.In addition, about the cultivation of the bacterium for counting, Staphylococcusaureus and E.Coli cultivates 3 days and 7 days respectively at 33 DEG C.It should be noted that, eucalyptus oil is the product meeting the 15th edition revision Pharmacopeia of Japan specification, and HCO60 is the product of the specification meeting pharmaceuticals additive specification 2003.Polyoxyethylene castor oil 10 is for meeting the product of the specification of the polyoxyethylene castor oil in pharmaceuticals additive specification 2003, and the average addition molal quantity of its ethylene oxide is 10.Result merging is shown in table 15.
[table 15]
Unit (w/v%)
Can be clear and definite from table 15, compared with the only compounding comparative example 5-6 of eucalyptus oil, the Staphylococcus aureus bacterium number in the compounding embodiment 5-4 having polyoxyethylene castor oil 10 and eucalyptus oil obviously reduces, and can confirm its high preservation effect.In addition, compare without impact with the bacterium number of comparative example 5-6 on E.Coli of only compounding eucalyptus oil, compounding have the bacterium number of visible E.Coli in the embodiment 5-4 of polyoxyethylene castor oil 10 and eucalyptus oil to reduce to some extent.
Known above, be polyoxyethylene castor oil and the terpenoid of 2 ~ 12 by the average addition molal quantity containing ethylene oxide, not only to StapHylococcus aureus, high preservation effect also demonstrated to E.Coli tool simultaneously.
[test example 14 sensory test]
The aqueous ophthalmic compositions (embodiment 6-1 and comparative example 6-1) of the composition of preparation shown in table 16, uses these aqueous ophthalmic compositions view-based access control model simulation scoring (VAS) to carry out the evaluation of refrigerant sense.Specifically, to 6 dripping property of panel discussion member ophthalmic compositions, for " the refrigerant sense " felt after firm instillation eye and after 5 minutes, subjective symptom application form is recorded the symptom degree that panel discussion member feels.Thereafter, according to subjective symptom application form, measure the intensity of subjective symptom with the form of length (cm), cannot feel refrigerant sense time be designated as 0cm, feel refrigerant sense time be designated as 5cm, be designated as 10cm when strongly feeling, calculate this length (cm) as refrigerant sense score.By the score averages of 6 panel discussion members after calculating just instillation eye, after 5 minutes, carry out the evaluation of refrigerant sense.Result is shown in table 16.
[table 16]
Unit (w/v%)
Shown in table 16, can confirm: the refrigerant sense score just after instillation eye is substantially equal, even if the aqueous ophthalmic compositions containing polyoxyethylene castor oil 10 also can feel obvious refrigerant sense at eye drip after 5 minutes.
Can be clear and definite by above result: and by the aqueous ophthalmic compositions of the present invention of polyoxyethylene castor oil 10 and terpenoid, there is the effect continuing the refrigerant sense keeping terpenoid.
[formulation example]
Prescription described in table 17 and table 18, conventionally prepares eye drop (formulation example 1 ~ 7), collyrium (formulation example 8), contact lens releives liquid (formulation example 9), contact lens multifunctional solution (formulation example 10).In addition, the unit of osmotic pressure is mOsm (milli infiltration mole).
[table 17]
[table 18]

Claims (12)

1. one kind is improved the method for antifoaming speed in aqueous ophthalmic compositions, it comprises: the average addition molal quantity of compounding in hydrotropism's ophthalmic composition (A) ethylene oxide is polyoxyethylene castor oil and (B) terpenoid of 2 ~ 12, and described terpenoid is be selected from more than one terpenoids in l-menthol, geraniol, eucalyptus oil, d-Camphora, d-Borneolum Syntheticum.
2. a suppression is accommodated in the method for aqueous ophthalmic compositions in the container deviation of dropping liquid amount in use, it comprises: the average addition molal quantity of compounding in hydrotropism's ophthalmic composition (A) ethylene oxide is polyoxyethylene castor oil and (B) terpenoid of 2 ~ 12, and described terpenoid is be selected from more than one terpenoids in l-menthol, geraniol, eucalyptus oil, d-Camphora, d-Borneolum Syntheticum.
3. method according to claim 2, wherein, the container of storage aqueous ophthalmic compositions is the polyethylene terephthalate container being provided with polyethylene nozzle.
4. one kind strengthens the method for the preservation effect of aqueous ophthalmic compositions, it comprises: the average addition molal quantity of compounding in hydrotropism's ophthalmic composition (A) ethylene oxide is polyoxyethylene castor oil and (B) terpenoid of 2 ~ 12, and described terpenoid is be selected from more than one terpenoids in l-menthol, geraniol, eucalyptus oil, d-Camphora, d-Borneolum Syntheticum.
5. one kind is suppressed the method for the separation of aqueous ophthalmic compositions, it comprises: the average addition molal quantity of compounding in hydrotropism's ophthalmic composition (A) ethylene oxide is polyoxyethylene castor oil and (B) terpenoid of 2 ~ 12, and described terpenoid is be selected from more than one terpenoids in l-menthol, geraniol, eucalyptus oil, d-Camphora, d-Borneolum Syntheticum.
6. a suppression be accommodated in the terpenoid substrate concentration of the aqueous ophthalmic compositions in container through time the method that reduces, it comprises: the average addition molal quantity of compounding in hydrotropism's ophthalmic composition (A) ethylene oxide is polyoxyethylene castor oil and (B) terpenoid of 2 ~ 12, and described terpenoid is be selected from more than one terpenoids in l-menthol, geraniol, eucalyptus oil, d-Camphora, d-Borneolum Syntheticum.
7. method according to claim 6, wherein, the container of storage aqueous ophthalmic compositions is the polyethylene terephthalate container being provided with polyethylene nozzle.
8. one kind maintains the method for the refrigerant sense of aqueous ophthalmic compositions, it comprises: the average addition molal quantity of compounding in hydrotropism's ophthalmic composition (A) ethylene oxide is polyoxyethylene castor oil and (B) terpenoid of 2 ~ 12, and described terpenoid is be selected from more than one terpenoids in l-menthol, geraniol, eucalyptus oil, d-Camphora, d-Borneolum Syntheticum.
9. an aqueous ophthalmic compositions, the average addition molal quantity of it contains (A) ethylene oxide is polyoxyethylene castor oil and (B) terpenoid of 2 ~ 12, and described terpenoid is be selected from more than one terpenoids in l-menthol, geraniol, eucalyptus oil, d-Camphora, d-Borneolum Syntheticum.
10. aqueous ophthalmic compositions according to claim 9, wherein, (A) composition is be selected from least one in the group that is made up of polyoxyethylene castor oil 3 and polyoxyethylene castor oil 10.
11. aqueous ophthalmic compositionss according to claim 9 or 10, it is further containing the nonionic surfactant beyond (A) composition.
12. aqueous ophthalmic compositionss according to any one of claim 9 ~ 11, it is filled in the container being provided with polyethylene nozzle.
CN201180063560.6A 2010-12-28 2011-12-27 Aqueous ophthalmic compositions Active CN103282052B (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
JP2010-292441 2010-12-28
JP2010292441 2010-12-28
PCT/JP2011/080163 WO2012090985A1 (en) 2010-12-28 2011-12-27 Aqueous ophthalmic composition

Publications (2)

Publication Number Publication Date
CN103282052A CN103282052A (en) 2013-09-04
CN103282052B true CN103282052B (en) 2015-08-12

Family

ID=46383079

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201180063560.6A Active CN103282052B (en) 2010-12-28 2011-12-27 Aqueous ophthalmic compositions

Country Status (7)

Country Link
US (2) US9034931B2 (en)
EP (1) EP2659911A4 (en)
JP (2) JP5810098B2 (en)
CN (1) CN103282052B (en)
BR (1) BR112013016897A2 (en)
HK (1) HK1186684A1 (en)
WO (1) WO2012090985A1 (en)

Families Citing this family (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP5922505B2 (en) * 2012-06-14 2016-05-24 ロート製薬株式会社 Glycyrrhizic acid-containing aqueous ophthalmic composition
JP6130741B2 (en) * 2012-06-15 2017-05-17 ロート製薬株式会社 Ophthalmic composition for soft contact lenses
JP5988855B2 (en) * 2012-06-27 2016-09-07 ロート製薬株式会社 Aqueous ophthalmic composition
JP6091780B2 (en) * 2012-07-09 2017-03-08 ロート製薬株式会社 Aqueous ophthalmic composition
US9427473B2 (en) 2012-12-04 2016-08-30 Rohto Pharmaceutical Co., Ltd. Aqueous ophthalmic composition
JP6304474B2 (en) * 2013-01-31 2018-04-04 ロート製薬株式会社 Eye drops
WO2015029926A1 (en) * 2013-08-26 2015-03-05 ロート製薬株式会社 Ophthalmological composition
WO2015080249A1 (en) * 2013-11-29 2015-06-04 ロート製薬株式会社 Aqueous composition for ophthalmological use or otolaryngological use
CN106456791B (en) * 2014-06-10 2021-08-10 日本乐敦制药株式会社 Ophthalmic aqueous composition
JP2017132764A (en) * 2016-01-27 2017-08-03 ロート製薬株式会社 Ophthalmic composition for silicone hydrogel color contact lenses
TWI743107B (en) 2016-04-22 2021-10-21 日商樂敦製藥股份有限公司 Combination of container and ophthalmic composition
JP2017197526A (en) * 2016-04-22 2017-11-02 ロート製薬株式会社 Ophthalmic composition
JP7387835B2 (en) * 2016-04-22 2023-11-28 ロート製薬株式会社 Ophthalmic composition
JP2017197524A (en) * 2016-04-22 2017-11-02 ロート製薬株式会社 Ophthalmic composition
JP7125250B2 (en) * 2016-04-22 2022-08-24 ロート製薬株式会社 ophthalmic composition
JP7159501B1 (en) * 2016-04-22 2022-10-24 ロート製薬株式会社 ophthalmic composition
US12082577B2 (en) 2016-09-29 2024-09-10 Jrx Biotechnology, Inc. Methods and compositions for modifying plant growth and reducing water consumption by plants
US11583496B2 (en) 2016-10-12 2023-02-21 PS Therapy Inc. Drug vehicle compositions and methods of use thereof
US11260035B2 (en) 2016-10-12 2022-03-01 Ps Therapies Ltd Topical compositions and methods of use thereof
TWI773706B (en) 2016-11-29 2022-08-11 瑞士商歐庫利斯公司 Preparation of solid cyclodextrin complexes for ophthalmic active pharmaceutical ingredient delivery
US11634368B2 (en) 2018-03-28 2023-04-25 Jrx Biotechnology, Inc. Agricultural compositions
JP7343964B2 (en) * 2018-09-21 2023-09-13 小林製薬株式会社 pharmaceutical composition
JP7451124B2 (en) * 2018-09-28 2024-03-18 ロート製薬株式会社 Oral composition and method for suppressing moisture absorption thereof
CA3142247A1 (en) 2019-07-01 2021-01-07 Oculis SA Method for stabilizing the ph of an aqueous composition comprising a drug

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6288049B1 (en) * 1998-01-22 2001-09-11 Santen Pharmaceutical Co., Ltd. Fluorometholone ophthalmic suspension

Family Cites Families (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5762218A (en) * 1980-10-01 1982-04-15 Lion Corp Ophthalmic solution
US5800389A (en) * 1996-02-09 1998-09-01 Emx, Inc. Biopsy device
JP3090125B2 (en) 1997-08-26 2000-09-18 千寿製薬株式会社 Ophthalmic composition for soft contact lens, method for enhancing wettability of soft contact lens, and method for suppressing adsorption of terpenoid
JP4274593B2 (en) * 1997-12-18 2009-06-10 ロート製薬株式会社 Eye drops for contact lenses containing a cooling agent
JP4748289B2 (en) 2000-06-23 2011-08-17 ライオン株式会社 Eye drops, ophthalmic composition, and adsorption suppression method
JP2002356420A (en) * 2001-03-27 2002-12-13 Santen Pharmaceut Co Ltd Stable aqueous solution
JP4748947B2 (en) 2003-04-04 2011-08-17 ロート製薬株式会社 Ophthalmic composition
KR20060040550A (en) 2004-11-05 2006-05-10 마루이시세이야쿠가부시키가이샤 Insulin-like growth factor-1 secretagogue
JP2006151971A (en) 2004-11-05 2006-06-15 Maruishi Pharmaceutical Co Ltd Insulin-like growth factor-1 secretion promoter
JP5092266B2 (en) 2005-04-18 2012-12-05 大正製薬株式会社 Ophthalmic agent
US20070015693A1 (en) 2005-07-13 2007-01-18 Allergan, Inc. Cyclosporin compositions
US20070148099A1 (en) 2005-12-27 2007-06-28 Burke Susan E Use of aroma compounds as defoaming agents for ophthalmic solutions with high concentrations of surfactants
MX2008011709A (en) * 2006-03-13 2008-09-24 R Tech Ueno Ltd Aqueous composition.
USRE43583E1 (en) * 2006-06-16 2012-08-14 Rohto Pharmaceutical Co., Ltd. Ophthalmic composition for soft contact lens comprising terpenoid
KR101475965B1 (en) * 2007-03-29 2014-12-23 산텐 세이야꾸 가부시키가이샤 Suspended eye drops containing fluorometholone
WO2009035034A1 (en) * 2007-09-14 2009-03-19 Rohto Pharmaceutical Co., Ltd. Ophthalmic composition
WO2012081673A1 (en) 2010-12-17 2012-06-21 ロート製薬株式会社 Ophthalmic composition for contact lens
WO2013008715A1 (en) 2011-07-08 2013-01-17 ロート製薬株式会社 Aqueous ophthalmic composition

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6288049B1 (en) * 1998-01-22 2001-09-11 Santen Pharmaceutical Co., Ltd. Fluorometholone ophthalmic suspension

Also Published As

Publication number Publication date
HK1186684A1 (en) 2014-03-21
US20130296446A1 (en) 2013-11-07
US20150209437A1 (en) 2015-07-30
US9034931B2 (en) 2015-05-19
BR112013016897A2 (en) 2019-09-24
JPWO2012090985A1 (en) 2014-06-05
US9320802B2 (en) 2016-04-26
JP2016028077A (en) 2016-02-25
JP5810098B2 (en) 2015-11-11
WO2012090985A1 (en) 2012-07-05
CN103282052A (en) 2013-09-04
EP2659911A4 (en) 2015-01-14
EP2659911A1 (en) 2013-11-06

Similar Documents

Publication Publication Date Title
CN103282052B (en) Aqueous ophthalmic compositions
JP7417365B2 (en) aqueous ophthalmic composition
JP7288289B2 (en) Aqueous ophthalmic composition
JP6596116B2 (en) Aqueous ophthalmic composition
JP6190503B2 (en) Aqueous ophthalmic composition
CN104797241B (en) aqueous ophthalmic composition
JP6177594B2 (en) Aqueous ophthalmic composition
CN103764168B (en) Aqueous ophthalmic compositions
JP6560764B2 (en) Ophthalmic composition
JP5922505B2 (en) Glycyrrhizic acid-containing aqueous ophthalmic composition
JP2023030691A (en) ophthalmic composition
CN109069421B (en) Ophthalmic composition
WO2025053197A1 (en) Ophthalmic composition
JP2024152702A (en) Ophthalmic composition for soft contact lenses
JP6091780B2 (en) Aqueous ophthalmic composition
CN104168885A (en) Aqueous pharmaceutical composition with enhanced stability

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
REG Reference to a national code

Ref country code: HK

Ref legal event code: DE

Ref document number: 1186684

Country of ref document: HK

C14 Grant of patent or utility model
GR01 Patent grant
REG Reference to a national code

Ref country code: HK

Ref legal event code: GR

Ref document number: 1186684

Country of ref document: HK